Malaria affects at least a billion people worldwide, and over 1.5 million infected children less than 5 years old die each year. Insect vector control programs have historically been an effective strategy for reducing disease transmission, but many malaria vectors have developed resistance to available insecticides. In partnership with Bayer, Astrazeneca and the broader industrially funded IRAC group, we will take an innovative approach to evaluate novel resistance management programs against pyrethroid resistant Anopheles funestus in Southern Africa. The field part of the program will determine whether we can drive back the current pyrethroid resistance front in Mozambique, that extends down into South Africa, using an annual insecticide rotation strategy. Coincident with this, a laboratory program will identify the molecular basis of pyrethroid resistance in this major malaria vector. We will work with our industrial partners initially to optimize the current management strategy, and subsequently to engineer synergists to specifically block the developing pyrethroid resistance. Synergists will be designed against the regulators of pyrethroid resistance in An. funestus and An. gambiae. The program will benefit from partnerships already established within the group to investigate similar resistance mechanisms in Anopheles gambiae from East Africa. If identical resistance regulatory mechanisms are operating in the two species it is possible that the synergist development and commercialization phase could occur within the time frame of this project. These synergists should in the medium term feed into the field-based resistance management program to expand the range of available vector control tools and extend the useful life of the pyrethroids within both indoor and residual spraying and impregnated bednet-based malaria control programmes.